Posterolateral Fusion Versus Posterior Lumbar Interbody Fusion for Adult Low-Grade Isthmic Spondylolisthesis: Analysis of Sagittal Radiographic Parameters - A Randomized Controlled Trial.

STUDY DESIGN: Randomized controlled trial. OBJECTIVES: To compare the effect of posterolateral fusion (PLF) and posterior lumbar interbody fusion (PLIF) on sagittal radiographic parameters in patients with low-grade isthmic spondylolisthesis. Additionally, to explore the correlation between changes in these parameters and clinical outcomes. METHODS: Forty-six consecutive patients with single-level low-grade isthmic spondylolisthesis were initially enrolled. They were randomly assigned to undergo either PLF or PLIF. Patients were followed up for at least 24 months. Radiographic outcomes included pelvic incidence, pelvic tilt, sacral slope, lumbar lordosis, sagittal vertical axis, T1 pelvic angle, slip angle, slip degree and disc height. Clinical outcomes were assessed by the Oswestry Disability Index (ODI) and visual analogue scale (VAS). RESULTS: Four participants were lost to follow-up. Of the remaining 42 patients, 29 were female. The mean age was 40.23 ± 10.25 years in the PLF group and 35.81 ± 10.58 years in the PLIF group. There was a statistically significant greater correction of all radiographic parameters in the PLIF group. The ODI and VAS improved significantly in both groups, with no significant differences between the two groups. Changes in the ODI and VAS were significantly correlated with changes in disc height, slip angle and lumbar lordosis. CONCLUSIONS: In patients with low-grade isthmic spondylolisthesis, PLIF demonstrates superior efficacy compared to PLF in correcting sagittal radiographic parameters. Nevertheless, this distinction does not seem to influence short-term clinical results. Restoring disc height, correcting the slip angle, and reestablishing normal lumbar lordosis are crucial steps in the surgical management of isthmic spondylolisthesis.

Autofusion in growing rod surgery for early onset scoliosis; what do we know so far?

The evolving landscape of early onset scoliosis management has shifted from the traditional paradigm of early definitive spinal fusion towards modern growth-friendly implants, particularly Growing Rods (GR). Despite the initial classification of GR treatment as a fusionless procedure, the phenomenon of autofusion has emerged as a critical consideration in understanding its outcomes. Studies have demonstrated the presence of autofusion since the early 1980s. The consequences of autofusion are extensive, impacting curve correction, diminishing trunk growth rate, and contributing to the "law of diminishing returns" in growing rod surgery. The literature suggests that autofusion may complicate definitive fusion surgery, leading to prolonged and intricate procedures involving multiple osteotomies. Additionally, it poses challenges in identifying anatomical landmarks during surgery, potentially increasing the risk of complications and revisions. While autofusion poses challenges to achieving optimal outcomes in growing rod treatment, it cannot be considered a standalone replacement for definitive fusion. Recent advances aim to limit autofusion and enhance treatment outcomes. In this review, we will delve into the existing literature on autofusion, examining studies that have documented its presence, probable causes, pathophysiology, potential implications for long-term patient outcomes, and possible new implants and techniques that decrease its incidence.

The Outcome of the WALANT Technique in Primary Hand Flexor Tendons Repair.

Introduction: Wide-awake local anesthesia and no tourniquet (WALANT) represents a revolutionary technique for hand surgeons who dismiss tourniquets and sedation. In this study, we present our experience with the WALANT technique in primary flexor tendon injuries of the hand. Patient and methods: This prospective research was carried out on 30 patients undergoing hand primary, flexor tendon repair surgery. Flexor tendon injury zones 2, 3, 4, and 5 were included. WALANT was prepared and injected. The tendons were surgically managed by a cruciate single cross-stitched locked 4-strand technique. The pain was assessed using a visual analog scale (VAS) score. The range of motion (ROM) of affected fingers was assessed according to the Strickland evaluation system. Results: There was a highly significant relationship between the patient's compliance with physiotherapy and obtained ROM of the affected finger with a P value <0.001. During injection of WALANT solution, 4 cases (13.3%) had no pain, 25 cases (83.3%) had mild pain (score 1-4), and 1 case (3.3%) had moderate pain (score 5-7). Conclusion: WALANT provides an optimal bloodless and comfortable field with an opportunity to assess the strength of tendon repair, gapping or triggering and managing them intra-operatively.

A Saudi Woman with Ceftriaxone Induced Fixed Drug Eruption.

Background: A fixed drug eruption (FDE) is an immunological cutaneous adverse reaction, classified as a cutaneous adverse drug reaction (CADR) and characterized by well-defined lichenoid lesions that occur at the same site each time. Ceftriaxone is a third-generation antibiotic of cephalosporin antibiotics of the beta-lactam antibiotic family, which has typical in vitro activity against many Gram-negative aerobic bacteria. This is the first clinical case from Saudi Arabia and the fifth in the world to document a woman's experience with recurrent FDE after repeated ceftriaxone use. Case Report. A 25-year-old Saudi woman with a known case of sickle cell anemia (SCA) with a history of avascular necrosis of the right hip after replacement was hospitalized with a pain crisis triggered by an upper respiratory tract infection. The patient denied having a history of allergy previously. Due to fever, leukocytosis, and active follicular tonsillitis, ceftriaxone was started. However, a few hours later she developed lip edema and a fixed drug eruption measuring 7 × 11 cm on the left side of her back. The lesion reformed over a hyperpigmented lesion (4 × 8 cm) that the patient did not report upon initial examination. It turned out that this was due to the intravenous administration of ceftriaxone, a year ago in another hospital. An allergy to ceftriaxone was considered, and steroids and antihistamines were started. The case was labeled as ceftriaxone induced FDE. Conclusion: Ceftriaxone induced FDE is an uncommon type of allergic reaction that has been reported infrequently. Understanding this condition and the mechanism by which FDE becomes recurrent with the same previous fixed lesion is of great importance for both academic and future research purposes.

Frankincense-Based Functionalized Multiwalled Carbon Nanotubes with Iron Oxide Composites for Efficient Removal of Crystal Violet: Kinetic and Equilibrium Analysis.

In this study, novel adsorbents were developed by functionalizing multiwalled carbon nanotubes with frankincense (Fr-fMWCNT) and adding iron oxide (Fe3O4) to the adsorbent (Fr-fMWCNT-Fe3O4). The morphology, surface characteristics, and chemical nature of the synthesized samples were analyzed by using various characterization techniques. The prepared adsorbents were then applied for the elimination of the toxic dye, crystal violet (CV), from water-based solutions by employing a batch adsorption method. The effectiveness of materials for the adsorption of CV was investigated by tuning various effective experimental parameters (adsorbent dosage, dye quantity, pH, and contact time). In order to derive adsorption isotherms, the Langmuir and Freundlich adsorption models were investigated and compared. The Fr-fMWCNT and Fr-fMWCNT-Fe3O4 were found to remove 85 and 95% of the CV dye within 30 min of the adsorption experiment at pH 6, respectively. It was found that a pseudo-second-order reaction rate was consistent with the experimental adsorption kinetics. The equilibrium data demonstrated that the Langmuir model adequately explained the adsorption behavior of the CV dye on the Fr-fMWCNT and Fr-fMWCNT-Fe3O4 surfaces, respectively. According to the Langmuir study, the highest adsorption capacities of the dye are 434 mg/g for Fr-fMWCNT and 500 mg/g for Fr-fMWCNT-Fe3O4. Remediation of the CV dye using our novel composite materials has not been reported previously in the literature. The synthesized Fr-fMWCNT and Fr-fMWCNT-Fe3O4 adsorbents can be economical and green materials for the adsorptive elimination of CV dye from wastewater.

An investigation of the acaricidal activity of benzyl alcohol on Rhipicephalus annulatus and Rhipicephalus sanguineus and its synergistic or antagonistic interaction with commonly used acaricides.

The most economically significant ectoparasites in the tropics and subtropics are ixodid ticks, especially Rhipicephalus annulatus and Rhipicephalus sanguineus. Years of extensive use of the readily available acaricides have resulted in widespread resistance development in these ticks, as well as negative environmental consequences. Benzyl alcohol (BA) has been frequently used to treat pediculosis and scabies, and it may be an effective alternative to commonly used acaricides. The main aim of the present study was to evaluate the acaricide activity of BA and its combination with the regularly used chemical acaricides against R. annulatus and R. sanguineus. Different concentrations of BA alone and in combination with deltamethrin, cypermethrin and chlorpyrifos were tested in vitro against adult and larvae of both tick species. The results showed that BA is toxic to R. annulatus and R. sanguineus larvae, with 100% larval mortality at concentrations of ≥50 mL/L, and LC50 and LC90 attained the concentrations of 19.8 and 33.8 mL/L for R. annulatus and 18.8 and 31.8 mL/L for R. sanguineus, respectively. Furthermore, BA in combination with deltamethrin, cypermethrin and chlorpyrifos exhibited synergistic factors of 2.48, 1.26 and 1.68 against R. annulatus larvae and 1.64, 11.1 and 1.14 against R. sanguineus larvae for deltamethrin + BA, cypermethrin + BA and chlorpyrifos + BA, respectively. BA induced 100% mortality in adult R. annulatus at concentrations of ≥250 mL/L with LC50 and LC90 reached the concentrations of 111 and 154 mL/L, respectively. Additionally, BA had ovicidal activity causing complete inhibition of larval hatching at 100 mL/L. The combination of BA with deltamethrin and cypermethrin increased acetylcholinesterase inhibition, whereas the combination of BA with chlorpyrifos decreased glutathione (GSH) activity and malondialdehyde levels. In the field application, the combination of BA 50 mL/L and deltamethrin (DBA) resulted in a significant reduction in the percentage of ticks by 30.9% 28 days post-treatment when compared with groups treated with deltamethrin alone. In conclusion, BA causes mortality in laboratory and field studies alone and in combination with cypermethrin or deltamethrin. BA can be used for control of ticks of different life stages, that is, eggs and larvae, through application to the ground.

Efficacy of D-Limonene Nanoemulsion Against Rhipicephalus annulatus and Rhipicephalus sanguineus Ticks.

PURPOSE: Ticks infestation has a negative impact against human and animal health through blood sucking, transmission of blood-borne diseases and also caused economic losses. METHODS: In the present study the adulticidal, ovicidal and larvicidal activity of D-limonene nanoemulsion (DLN) were evaluated against two tick species; Rhipicephalus annulatus and Rhipicephalus sanguineus. Nanoemulsion form of D-limonene was prepared, and its characteristics were evaluated using a UV spectrophotometer and zeta droplet size measurement. Acetylcholinesterase activity was determined. RESULTS: The results revealed significant adulticidal effect with low LC50 and LC90 for D-limonene pure form (DL) against both adult tick spp. (R. annulatus and R. sanguineus) ((0.958 and 1.559%) and (2.26 and 3.51%), respectively). DLN LC50 and LC90 values were ((1.277 and 2.396) and (3.97 and 7.28), respectively) against R. annulatus and R. sanguineus, respectively. DL and DLN showed significant ovicidal effect against R. sanguineus at high concentrations (10 and 5%). In larval packet test, LC50 and LC90 values of DL were ((1.53 and 2.22%) and (6.81 and 12.07%), respectively) against R. annulatus and R. sanguineus, respectively, while LC50 and LC90 values of DLN were ((6.48 and 11.26%) and (7.82 and 13.59%), respectively) against R. annulatus and R. sanguineus, respectively. Significant acetylcholinesterase inhibition percentage was detected for both ticks spp. which treated by DL and DLN. CONCLUSION: Pure DL is more effective than DLN form against R. annulatus and R. sanguineus.

Clinical Outcomes With Pembrolizumab-Based Therapies in Recurrent/Refractory NSCLC After Chemoradiation and Consolidative Durvalumab.

BACKGROUND: Often, patients with NSCLC experience recurrent/refractory (R/R) disease within 2 years of chemoradiation (CRT) and consolidative durvalumab. Despite prior immune checkpoint inhibitor exposure, immunotherapy with or without chemotherapy is typically initiated if a driver-oncogene is absent. However, there remains a paucity of data regarding the efficacy of immunotherapy in this patient population. Here, we present survival outcomes associated with pembrolizumab for R/R NSCLC. MATERIALS AND METHODS: We retrospectively assessed adults with NSCLC who received pembrolizumab for R/R disease between January 2016 to January 2023. Primary objective was to estimate OS and PFS in this cohort compared to historical outcomes. Secondary objective was to compare OS and PFS among subgroups. RESULTS: Fifty patients were evaluated. Median follow-up time was 11.3 months (2.9-38.2). OS was 10.6 months (95% CI, 8.8-19.2); 1-year OS rate 49% (95% CI, 36 - 67%). PFS was 6.1 months (95% CI, 4.7-9.0); 1-year PFS rate 25% (95% CI, 15%-42%). Current smokers had significantly better median OS/PFS as compared to former smokers (NA vs. 10.5 and 9.9 vs. 6.0 months, respectively). The addition of chemotherapy demonstrated an OS benefit (median OS 12.9 vs. 6.0 months) but was not statistically significant. CONCLUSION: Patients with R/R NSCLC represent a distinct cohort with inferior survival outcomes when compared to those with de novo stage IV disease treated with pembrolizumab-based regimens. Based on our findings, we recommend oncologists exercise caution when considering checkpoint inhibitor monotherapy in the front-line setting for R/R NSCLC, regardless of PD-L1 expression.

Safety and Efficacy of Pure and a Nanosuspension of D-limonene for Controlling Pigeon Lice.

This study investigated the safety and efficacy of two forms of D-limonene (DL) against Columbicola columbae (pigeon feather lice); pure and a nanoemulsion formulation (DLN). The cell cytotoxicity of the prepared forms of DL/DLN was investigated using skin cell lines. In vitro and ex vivo bioassays were applied on lice. The ex vivo bioassay was done on cut feathers containing lice eggs. The in vivo experiment was conducted on pigeons naturally infested by lice. The infested pigeons were treated with DL, DLN, or deltamethrin (D) as a positive control. Both forms of D-limonene were found to be safe when applied to the normal human skin fibroblast cell line, but DLN was toxic to skin cell carcinoma. The in vitro and ex vivo results of both DL and DLN forms were similar. All eggs treated with DL, DLN, and D failed to hatch (100%). The in vivo results showed complete elimination of lice 24 h post-treatment (PT), and biochemical analysis showed that the treated birds retained normal kidney and liver functions. Treated groups also showed improved productivity in the 4 months PT. In conclusion, DL and DLN are safe and effective in controlling feather lice infestation in pigeons and successful treatment encourages bird productivity.

D-limonene nanoemulsion: lousicidal activity, stability, and effect on the cuticle of Columbicola columbae.

The current study was conducted to investigate the efficacy and stability of D-limonene (DL) and its nanoemulsion (DLN) against pigeon feather lice (Columbicola columbae) and their mode of action. DL pure form and DLN were prepared and characterized freshly and after storage for 50 days. In vitro bioassay on live lice was conducted with different concentrations of DL, DLN, and deltamethrin (DM). The results revealed significant mortality rates in the DL-, DLN-, DM-treated groups when compared with the control (p < 0.05). The scanning electron micrographs of lice treated with DL and DLN revealed collapsed bodies with destruction in the cuticle of the mouthparts and damaged antennae. The 50 days stored DLN showed stability in their effectiveness when compared with the freshly prepared formulation. DL and DLN caused significant inhibition (p ≤ 0.05) in acetylcholinesterase activity (AchE). Malondialdehyde level (MDA) was significantly increased while glutathione was significantly decreased in DL- and DLN-treated lice. In conclusion, DL and DLN have significant lousicidal activities. DLN showed better stability than DL after storage for 50 days. In addition, the mode of action of DL may associate with its effect on the cuticle of the lice body, inhibition of AchE, and increasing oxidative stress in the treated lice.

Role of antioxidant activity of essential oils in their acaricidal activities against Rhipicephalus annulatus.

Essential oils of Origanum majorana and Satureja thymbra as well as carvacrol are natural products that are known to have potent antioxidant activities. The current study was designed to investigate the role of the antioxidant properties of these natural products in their acaricidal activities against Rhipicephalus annulatus larvae. The synergistic and/or antagonistic effects of the addition of vitamins E and C and hydrogen peroxide (H2O2) to these natural products were also evaluated. Larval packet tests were used to evaluate the acaricidal activities against the larvae of R. annulatus. The antioxidant effectiveness of these products was determined by a DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical scavenging assay. The addition of vitamin E at 100 mg/mL to O. majorana and S. thymbra decreased the concentrations required to achieve the death of half of the larvae (LC50) to 0.44 and 0.47%, respectively. The combination of O. majorana and S. thymbra attained the LC50 at 1.54% which was decreased to 0.69% after addition of vitamin E. Also, the addition of vitamin E to carvacrol reduced the LC50 to 0.27%. The total antioxidant activity of these natural products increased significantly in presence of vitamin E. The addition of H2O2 inhibited the acaricidal activity of all tested materials, especially at low concentrations. All treatments induced an increase in lipid peroxidation, whereas carvacrol-treated larvae revealed the lowest values for the superoxide dismutase. Glutathione peroxidase and catalase activity decreased in larvae treated with S. thymbra combined with vitamin E. In conclusion, the addition of vitamins E and C increased the acaricidal activities of the tested compounds, whereas the addition of H2O2 decreased these activities. The antioxidant activities of essential oils and their active components may play an important role in mediating their acaricidal activities.

Understanding the Controlling Factors for CO2 Sequestration in Depleted Shale Reservoirs Using Data Analytics and Machine Learning.

Carbon capture and sequestration is the process of capturing carbon dioxide (CO2) from refineries, industrial facilities, and major point sources such as power plants and storing the CO2 in subsurface formations. Carbon capture and sequestration has the potential to generate an industry comparable to, if not greater than, the existing oil and gas sector. Subsurface formations such as unconventional oil and gas reservoirs can store significant quantities of CO2. Despite their importance in the oil and gas industry, our understanding of CO2 sequestration in unconventional reservoirs still needs to be developed. The objective of this paper was to use an extensive data set of numerical simulation results combined with data analytics and machine learning to identify the key parameters that affect CO2 sequestration in depleted shale reservoirs. Machine learning-based predictive models based on multiple linear regression, regression tree, bagging, random forest, and gradient boosting were built to predict the cumulative CO2 injected. Variable importance was carried out to identify and rank important reservoir and operational parameters. The results showed that random forest provided the best predictive ability among the machine learning techniques and that regression tree had the worst predictive ability, mainly because of overfitting. The most significant variable for predicting cumulative CO2 sequestration was stimulated reservoir volume fracture permeability. The workflows, machine learning models, and results reported in this study provide insights for exploration and production companies interested in quantifying CO2 sequestration performance in shale reservoirs.

Frequency of Neuropathic Sensory Symptoms Among Patients With Uncontrolled Diabetes Mellitus in Security Forces Hospital, Riyadh, Saudi Arabia.

Background Diabetic peripheral neuropathy (DPN) is a chronic sensorimotor length-dependent and symmetrical polyneuropathy. Some peripheral neuropathies have painful presentations, and some are painless. DPN can have a potential impact on the patient's life. Objectives This study was conducted in order to investigate the frequency of neuropathic sensory symptoms among patients with uncontrolled diabetes mellitus. Methods This is a cross-sectional study conducted in the Security Forces hospital using the Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire. The questionnaire was administered by contacting patients through the phone. Patients with uncontrolled diabetes (HbA1C >9) were included in the study. Results This study included 285 participants; 58.9% had type II diabetes and 41.1% had type I diabetes, 156 (54.7%) were females, and 129 (45.3%) were males. Most of the patients (51.1%) were 45-64 years old and the majority were non-smokers (77.9%). Patients with neuropathic pain were 182 (63.9%); 79 (43.4%) of them were males and 103 (56.6%) were females. The prevalence of neuropathic symptoms was much higher in females than in males. Conclusion The prevalence of painful DPN is high among patients with long-term uncontrolled diabetes mellitus. Older, unemployed, and low-educated patients are at higher risk of developing painful DPN. Proper glycemic control and lifestyle modifications are essential in preventing the progression of this condition.

Validation of a translated version of the modified Japanese Orthopedic Association (mJOA) cervical myelopathy score in an Arabic speaking population.

INTRODUCTION: Degenerative Cervical Myelopathy (DCM) is a growing disorder. Standardization of its assessment tools is an integral part of its management. The modified Japanese orthopedic association (mJOA) score is one of the most commonly used tools. Currently, there is no available Arabic translated version of any cervical myelopathy functional score. This study aimed to translate, culturally adapt, and measure the psychometric properties of an Arabic translated version of the mJOA. METHODS: After translation of the score using the standard forward-backward translation procedure, a validation study including 100 patients was carried out from June 2019 to June 2020. The following psychometric properties were measured: feasibility, reliability, internal consistency, validity, minimal clinically important difference (MCID), ceiling, and floor effect. RESULTS: No problems were encountered during the process of translation and cross-cultural adaptation of the score. The mJOA-AR was found to be a feasible score. It showed high inter-observer reliability (r = 0.833, P < 0.001), test-retest reliability (r = 0.987, P < 0.001) and good internal consistency using Cronbach's alpha (0.777) and Pearson interclass correlation coefficient (r = 0.717). The score showed good convergent and divergent construct validity correlating it to the Arabic validated version of the neck disability index (NDI). The mJOA-AR had an MCID of 1.506. Both the ceiling and floor effects of the total score and the first and second domains were within the acceptable range, while the third and fourth domains had a high ceiling effect (30% and 39%, respectively). DISCUSSION: Our translated version of the mJOA score was found to be a feasible score with acceptable psychometric properties. This score can be utilized as a good outcome measure tool in Arabic-speaking countries.

Bone Metastases, Skeletal-Related Events, and Survival in Patients With Metastatic Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.

BACKGROUND: Bone metastases and skeletal-related events (SREs) are a frequent cause of morbidity in patients with metastatic non-small cell lung cancer (mNSCLC). Data are limited on bone metastases and SREs in patients with mNSCLC treated using immune checkpoint inhibitors (ICIs), and on the efficacy of bone-modifying agents (BMAs) in this setting. Here we report the incidence, impact on survival, risk factors for bone metastases and SREs, and impact of BMAs in patients with mNSCLC treated with ICIs in a multi-institutional cohort. PATIENTS AND METHODS: We conducted a retrospective study of patients with mNSCLC treated with ICIs at 2 tertiary care centers from 2014 through 2017. Overall survival (OS) was compared between patients with and without baseline bone metastases using a log-rank test. A Cox regression model was used to evaluate the association between OS and the presence of bone metastases at ICI initiation, controlling for other confounding factors. RESULTS: We identified a cohort of 330 patients who had received ICIs for metastatic disease. Median patient age was 63 years, most patients were treated in the second line or beyond (n=259; 78%), and nivolumab was the most common ICI (n=211; 64%). Median OS was 10 months (95% CI, 8.4-12.0). In our cohort, 124 patients (38%) had baseline bone metastases, and 43 (13%) developed SREs during or after ICI treatment. Patients with bone metastases had a higher hazard of death after controlling for performance status, histology, line of therapy, and disease burden (hazard ratio, 1.57; 95% CI, 1.19-2.08; P=.001). Use of BMAs was not associated with OS or a decreased risk of SREs. CONCLUSIONS: Presence of bone metastases at baseline was associated with a worse prognosis for patients with mNSCLC treated with ICI after controlling for multiple clinical characteristics. Use of BMAs was not associated with reduced SREs or a difference in survival.

Optimal Data Collection Time in LoRa Networks-A Time-Slotted Approach.

LoRa is a low-power and long range radio communication technology designed for low-power Internet of Things devices. These devices are often deployed in remote areas where the end-to-end connectivity provided through one or more gateways may be limited. In this paper, we examine the case where the gateway is not available at all times. As a consequence, the sensing data need to be buffered locally and transmitted as soon as a gateway becomes available. However, due to the Aloha-style transmission policy of current LoRa-based standards, such as the LoRaWAN, delivering a large number of packets in a short period of time by a large number of nodes becomes impossible. To avoid bursts of collisions and expedite data collection, we propose a time-slotted transmission scheduling mechanism. We formulate the data scheduling optimisation problem, taking into account LoRa characteristics, and compare its performance to low complexity heuristics. Moreover, we conduct a set of simulations to show the benefits of synchronous communications on the data collection time and the network performance. The results show that the data collection can reliably be achieved at least 10 times faster compared to an Aloha-based approach for networks with 100 or more nodes. We also develop a proof-of-concept to assess the overhead cost of communicating the schedule to the nodes and we present experimental results.

High-Throughput Label-Free Isolation of Heterogeneous Circulating Tumor Cells and CTC Clusters from Non-Small-Cell Lung Cancer Patients.

(1) Background: Circulating tumor cell (CTC) clusters are emerging as clinically significant harbingers of metastases in solid organ cancers. Prior to engaging these CTC clusters in animal models of metastases, it is imperative for technology to identify them with high sensitivity. These clusters often present heterogeneous surface markers and current methods for isolation of clusters may fall short. (2) Methods: We applied an inertial microfluidic Labyrinth device for high-throughput, biomarker-independent, size-based isolation of CTCs/CTC clusters from patients with metastatic non-small-cell lung cancer (NSCLC). (3) Results: Using Labyrinth, CTCs (PanCK+/DAPI+/CD45-) were isolated from patients (n = 25). Heterogeneous CTC populations, including CTCs expressing epithelial (EpCAM), mesenchymal (Vimentin) or both markers were detected. CTCs were isolated from 100% of patients (417 ± 1023 CTCs/mL). EpCAM- CTCs were significantly greater than EpCAM+ CTCs. Cell clusters of ≥2 CTCs were observed in 96% of patients-of which, 75% were EpCAM-. CTCs revealed identical genetic aberrations as the primary tumor for RET, ROS1, and ALK genes using fluorescence in situ hybridization (FISH) analysis. (4) Conclusions: The Labyrinth device recovered heterogeneous CTCs in 100% and CTC clusters in 96% of patients with metastatic NSCLC. The majority of recovered CTCs/clusters were EpCAM-, suggesting that these would have been missed using traditional antibody-based capture methods.

A Pilot Study of Atezolizumab Plus Hypofractionated Image Guided Radiation Therapy for the Treatment of Advanced Non-Small Cell Lung Cancer.

PURPOSE: Preclinical data and subset analyses from immunotherapy clinical trials indicate that prior radiation therapy was associated with better progression-free survival and overall survival when combined with immune checkpoint inhibitors in patients with non-small cell lung cancer. We present a prospective study of hypofractionated image guided radiation therapy (HIGRT) to a single site of metastatic disease concurrently with atezolizumab in patients with metastatic non-small cell lung cancer. METHODS AND MATERIALS: Patients meeting eligibility criteria received 1200 mg of atezolizumab intravenously every 3 weeks with concurrent 3- or 5-fraction HIGRT starting no later than the second cycle. The 3-fraction regimen employed a minimum of 8 Gy per fraction compared with 6 Gy for the 5-fraction regimen. Imaging was obtained every 12 weeks to assess response. RESULTS: From October 2015 to February 2017, 12 patients were enrolled in the study (median age 64; range, 55-77 years). The best response by the Response Evaluation in Solid Tumors criteria was partial response in 3 and stable disease in 3, for a disease control rate of 50%. Five patients had a grade 3 immune-related adverse event, including choreoretinitis (n = 1), pneumonitis (n = 1), transaminitis (n = 1), fatigue (n = 1), and peripheral neuropathy (n = 1). The median progression-free survival was 2.3 months, and the median overall survival was 6.9 months (range, 0.4-not reached). There was no clear association between peripheral blood T cell repertoire characteristics at baseline, PD-L1, or tumor mutations and response or outcome. One long-term survivor exhibited oligoclonal T cell populations in a baseline tumor biopsy that were consistently detected in peripheral blood over the entire course of the study. CONCLUSIONS: HIGRT plus atezolizumab resulted in an overall response rate of 25% and disease control rate of 50% in this pilot study. The incidence of grade 3 adverse events was similar to that of atezolizumab alone. Alhough it was a pilot study with limited sample size, the results generated hypotheses worthy of further investigation.